bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2023–09–17
28 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Mitochondrial degradation: Mitophagy and beyond.
  2. PKR activation in mitochondrial unfolded protein response-mitochondrial dsRNA might do the trick.
  3. Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency.
  4. Elevated susceptibility to exogenous seizure triggers and impaired interneuron excitability in a mouse model of Leigh syndrome epilepsy.
  5. Generation of two human iPSC lines, HMGUi004-A and FINCBi004-A, from fibroblasts of MPAN patients carrying pathogenic recessive mutations in the gene C19orf12.
  6. Schizophrenia-Like Psychotic Symptoms Associated to Leigh Syndrome.
  7. Mit.OnOff: A Science Communication Project for Public Awareness about Mitochondrial Cytopathies.
  8. Molecular pathway of mitochondrial preprotein import through the TOM-TIM23 supercomplex.
  9. Mitochondrial GTP metabolism controls reproductive aging in C. elegans.
  10. Novel pathogenic UQCRC2 variants in a female with normal neurodevelopment.
  11. Skeletal muscle mitochondria in strength athletes: meeting energy needs with mitochondrial morphological changes.
  12. Friedreich's ataxia: new insights.
  13. Mitochondrial dysfunction in neurodegenerative disorders: Potential therapeutic application of mitochondrial transfer to central nervous system-residing cells.
  14. Alternative to lysosomal degradation: mitochondrial removal via EVs.
  15. Early steps in the biogenesis of mitochondrially encoded oxidative phosphorylation subunits.
  16. Cardiolipin prolongs the lifetimes of respiratory proteins in Drosophila flight muscle.
  17. Outer mitochondrial membrane E3 Ub ligase MARCH5 controls mitochondrial steps in peroxisome biogenesis.
  18. Sirtuin-3 activates the mitochondrial unfolded protein response and reduces cerebral ischemia/reperfusion injury.
  19. Mesenchymal stem cell attenuates spinal cord injury by inhibiting mitochondrial quality control-associated neuronal ferroptosis.
  20. Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a Friedreich's ataxia mouse model.
  21. Trazodone rescues dysregulated synaptic and mitochondrial nascent proteomes in prion neurodegeneration.
  22. Nrf2 depletion in the context of loss-of-function Keap1 leads to mitolysosome accumulation.
  23. Molecular control of endurance training adaptation in male mouse skeletal muscle.
  24. Illuminating the human yolk sac through single-cell omics.
  25. Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation.
  26. Mitochondria Derived Vesicle Packaging as a Novel Therapeutic Mechanism in Pulmonary Hypertension.
  27. The association between methylmalonic acid, a biomarker of mitochondria dysfunction, and phenotypic age acceleration: A population-based study.
  28. A patient with MELAS syndrome combined with autoimmune abnormalities: a case report.
  1. Mol Cell. 2023 Sep 07. pii: S1097-2765(23)00656-1. [Epub ahead of print]
    Mitochondrial degradation: Mitophagy and beyond.
    Louise Uoselis, Thanh Ngoc Nguyen, Michael Lazarou.
      Mitochondria are central hubs of cellular metabolism that also play key roles in signaling and disease. It is therefore fundamentally important that mitochondrial quality and activity are tightly regulated. Mitochondrial degradation pathways contribute to quality control of mitochondrial networks and can also regulate the metabolic profile of mitochondria to ensure cellular homeostasis. Here, we cover the many and varied ways in which cells degrade or remove their unwanted mitochondria, ranging from mitophagy to mitochondrial extrusion. The molecular signals driving these varied pathways are discussed, including the cellular and physiological contexts under which the different degradation pathways are engaged.
    Keywords:  MDV; PINK1; Parkin; degradation; mitochondria; mitochondrial quality control; mitophagy; proteasome; selective autophagy; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.021
  2. Front Cell Dev Biol. 2023 ;11 1270341
    PKR activation in mitochondrial unfolded protein response-mitochondrial dsRNA might do the trick.
    Eva Rath.
      
    Keywords:  double-stranded RNA-activated protein kinase; doublestranded RNA; inflammatory bowel diseases; integrated stress response; mitochondria; mitochondrial unfolded protein response; proteostasis; stress signaling
    DOI:  https://doi.org/10.3389/fcell.2023.1270341
  3. Dis Model Mech. 2023 Sep 11. pii: dmm.050114. [Epub ahead of print]
    Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency.
    Nicole M Sayles, Jill S Napierala, Josef Anrather, Nadège Diedhiou, Jixue Li, Marek Napierala, Hélène Puccio, Giovanni Manfredi.
      Cardiomyopathy is often fatal in Friedreich Ataxia (FA). However, FA hearts maintain adequate function until advanced disease stages, suggesting initial adaptation to the loss of frataxin (FXN). Conditional cardiac knockout mouse models of FXN show transcriptional and metabolic profiles of the mitochondrial integrated stress response (ISRmt), which could play an adaptive role. However, ISRmt has not been investigated in models with disease-relevant, partial decrease of FXN. We characterized the heart transcriptomes and metabolomes of three mouse models with varying degrees of FXN depletion, YG8-800, KIKO-700, and FxnG127V. Few metabolites were changed in YG8-800 mice and did not provide a signature of cardiomyopathy or ISRmt. Instead, several metabolites were altered in FxnG127V and KIKO-700 hearts. Transcriptional changes were found in all models, but differentially expressed genes consistent with cardiomyopathy and ISRmt were only identified in FxnG127V hearts. However, these changes were surprisingly mild even at an advanced age (18-months), despite a severe decrease in FXN levels to 1% of WT. These findings indicate that the mouse heart has low reliance on FXN, highlighting the difficulty in modeling genetically relevant FA cardiomyopathy.
    Keywords:  Cardiomyopathy; Frataxin; Friedreich Ataxia; Integrated stress response; Mitochondria; Mouse model
    DOI:  https://doi.org/10.1242/dmm.050114
  4. Neurobiol Dis. 2023 Sep 11. pii: S0969-9961(23)00303-0. [Epub ahead of print] 106288
    Elevated susceptibility to exogenous seizure triggers and impaired interneuron excitability in a mouse model of Leigh syndrome epilepsy.
    Arena Manning, Victor Han, Alexa Stephens, Rose Wang, Nicholas Bush, Michelle Bard, Jan M Ramirez, Franck Kalume.
      Mutations in the NADH dehydrogenase (ubiquinone reductase) iron‑sulfur protein 4 (NDUFS4) gene, which encodes for a key structural subunit of the OXFOS complex I (CI), lead to the most common form of mitochondrial disease in children known as Leigh syndrome (LS). As in other mitochondrial diseases, epileptic seizures constitute one of the most significant clinical features of LS. These seizures are often very difficult to treat and are a sign of poor disease prognosis. Mice with whole-body Ndufs4 KO are a well-validated model of LS; they exhibit epilepsy and several other clinical features of LS. We have previously shown that mice with Ndufs4 KO in only GABAergic interneurons (Gad2-Ndufs4-KO) reproduce the severe epilepsy phenotype observed in the global KO mice. This observation indicated that these mice represent an excellent model of LS epilepsy isolated from other clinical manifestations of the disease. To further characterize this epilepsy phenotype, we investigated seizure susceptibility to selected exogenous seizure triggers in Gad2-Ndufs4-KO mice. Then, using electrophysiology, imaging, and immunohistochemistry, we studied the cellular, physiological, and neuroanatomical consequences of Ndufs4 KO in GABAergic interneurons. Homozygous KO of Ndufs4 in GABAergic interneurons leads to a prominent susceptibility to exogenous seizure triggers, impaired interneuron excitability and interneuron loss. Finally, we found that the hippocampus and cortex participate in the generation of seizure activity in Gad2-Ndufs4-KO mice. These findings further define the LS epilepsy phenotype and provide important insights into the cellular mechanisms underlying epilepsy in LS and other mitochondrial diseases.
    Keywords:  Epilepsy; Excitability; GABAergic interneuron; Ndufs4; Seizures; hippocampus
    DOI:  https://doi.org/10.1016/j.nbd.2023.106288
  5. Stem Cell Res. 2023 Sep 01. pii: S1873-5061(23)00183-6. [Epub ahead of print]72 103197
    Generation of two human iPSC lines, HMGUi004-A and FINCBi004-A, from fibroblasts of MPAN patients carrying pathogenic recessive mutations in the gene C19orf12.
    Enrica Zanuttigh, Ejona Rusha, Camille Peron, Dario Brunetti, Giovanna Zorzi, Anna Pertek, Polyxeni Nteli, Juliane Winkelmann, Valeria Tiranti, Arcangela Iuso.
      Mitochondrial membrane Protein-Associated Neurodegeneration (MPAN) is a lethal neurodegenerative disorder caused by mutations in the human gene C19orf12. The molecular mechanisms underlying the disorder are still unclear, and no established therapy is available. Here, we describe the generation and characterization of two human induced pluripotent stem cell (iPSC) lines derived from skin fibroblasts of two MPAN patients carrying homozygous recessive mutations in C19orf12. These iPSC lines represent a useful resource for future investigations on the pathology of MPAN, as well as for the development of successful treatments.
    DOI:  https://doi.org/10.1016/j.scr.2023.103197
  6. Case Rep Psychiatry. 2023 ;2023 8886555
    Schizophrenia-Like Psychotic Symptoms Associated to Leigh Syndrome.
    F Jaballah, R Ben Soussia Nouira, S Mallouli, H Boussaid, S Younes, L Zarrouk, S Younes.
       Introduction: Leigh syndrome (LS) is a mitochondrial disease characterized by subacute necrotizing encephalomyelopathy with an estimated incidence of 1:40,000 births. The comorbidity of psychotic symptoms noted in mitochondrial and psychiatric diseases has spurred interest in the effects of DNA mutations and psychiatric disorders. Case presentation. We report the case of a Tunisian 28-year-old male diagnosed with maternally inherited Leigh syndrome. He presented anxiety and auditory hallucinations, and he reported a vague, unsystematized delusion evolving since 6 months. Significant remission was observed at risperidone 3 mg/day. Discussion. The normality of explorations in our case raised the issue of the link between the two diseases, supporting the hypothesis that mitochondrial dysfunction maybe the primary origin of psychotic disorders.
    Conclusion: The aim of our work is to study the relations between mitochondrial dysfunction and psychiatric symptoms. Further study of mitochondrial dysfunction in psychiatric disorders is expected to be useful for the development of cellular disease markers and new psychotropics.
    DOI:  https://doi.org/10.1155/2023/8886555
  7. Endocr Metab Immune Disord Drug Targets. 2023 Sep 14.
    Mit.OnOff: A Science Communication Project for Public Awareness about Mitochondrial Cytopathies.
    Manuela Grazina, Sara Martins, Maria João Santos, Marta Simões, Carolina Caetano, Beatriz Neves, Sara Varela Amaral, Laurence A Bindoff.
       INTRODUCTION: Mitochondrial diseases are rare, heterogeneous, incurable and complex to diagnose. Probably due to their rareness, there is still a lack of literacy in this area, especially in society, but also in schools and in general, health care services. Accordingly, tools that may bring advancement in science and health literacy are needed. Mit.OnOff is a science communication project based on a bilateral partnership between the University of Coimbra (Portugal) and the University of Bergen (Norway). It aims to inform society about rare diseases related to mitochondrial cytopathies with an emphasis on LHON.
    METHODS: The initiative focuses on the creation of an illustrated book explaining the diseases caused by the failure of energy production in simple and accessible language. The aim is to raise awareness (particularly in Portugal and Norway) and provide in-depth knowledge to people suffering from these diseases.
    RESULTS/CASE REPORT: This project involves expert scientists in the field of mitochondrial disease, science communicators and artists in alignment with the United Nations SDGs, Agenda 2030. Mit.OnOff is a bilateral partnership (Portugal and Norway) established to address the lack of knowledge and health literacy on the subject of mitochondrial disease. The book will be distributed in both countries, creating a sense of inclusion and visibility and influencing decisions regarding these diseases. It is a relevant educational medium (e.g., schools, health care provision). The distribution of the book is complemented with other communication materials. Oral communications are made, together with public involvement, in which special glasses will be distributed to simulate a mitochondrial disease that leads to blindness (LHON) for the public to experience what it is like living with a rare disease.
    CONCLUSION: It is hoped that the production of this book will give patients a sense of inclusion and representation in the media. This, in turn, will contribute to achieving the SDG targets (3,4,5,8,10,12), i.e., ensuring people live healthy lives, reducing child mortality, and increasing life expectancy, ensuring access to inclusive, equitable and quality education for all, ensuring gender equality, and contributing to a peaceful and prosperous world.
    Keywords:  LHON; health literacy; mitochondria; mitochondrial cytopathies; mitochondrial diseases; rare diseases; science communication
    DOI:  https://doi.org/10.2174/1871530323666230914114434
  8. Nat Struct Mol Biol. 2023 Sep 11.
    Molecular pathway of mitochondrial preprotein import through the TOM-TIM23 supercomplex.
    Xueyin Zhou, Yuqi Yang, Guopeng Wang, Shanshan Wang, Dongjie Sun, Xiaomin Ou, Yuke Lian, Long Li.
      Over half of mitochondrial proteins are imported from the cytosol via the pre-sequence pathway, controlled by the TOM complex in the outer membrane and the TIM23 complex in the inner membrane. The mechanisms through which proteins are translocated via the TOM and TIM23 complexes remain unclear. Here we report the assembly of the active TOM-TIM23 supercomplex of Saccharomyces cerevisiae with translocating polypeptide substrates. Electron cryo-microscopy analyses reveal that the polypeptide substrates pass the TOM complex through the center of a Tom40 subunit, interacting with a glutamine-rich region. Structural and biochemical analyses show that the TIM23 complex contains a heterotrimer of the subunits Tim23, Tim17 and Mgr2. The polypeptide substrates are shielded from lipids by Mgr2 and Tim17, which creates a translocation pathway characterized by a negatively charged entrance and a central hydrophobic region. These findings reveal an unexpected pre-sequence pathway through the TOM-TIM23 supercomplex spanning the double membranes of mitochondria.
    DOI:  https://doi.org/10.1038/s41594-023-01103-7
  9. Dev Cell. 2023 Sep 07. pii: S1534-5807(23)00435-5. [Epub ahead of print]
    Mitochondrial GTP metabolism controls reproductive aging in C. elegans.
    Yi-Tang Lee, Marzia Savini, Tao Chen, Jin Yang, Qian Zhao, Lang Ding, Shihong Max Gao, Mumine Senturk, Jessica N Sowa, Jue D Wang, Meng C Wang.
      Healthy mitochondria are critical for reproduction. During aging, both reproductive fitness and mitochondrial homeostasis decline. Mitochondrial metabolism and dynamics are key factors in supporting mitochondrial homeostasis. However, how they are coupled to control reproductive health remains unclear. We report that mitochondrial GTP (mtGTP) metabolism acts through mitochondrial dynamics factors to regulate reproductive aging. We discovered that germline-only inactivation of GTP- but not ATP-specific succinyl-CoA synthetase (SCS) promotes reproductive longevity in Caenorhabditis elegans. We further identified an age-associated increase in mitochondrial clustering surrounding oocyte nuclei, which is attenuated by GTP-specific SCS inactivation. Germline-only induction of mitochondrial fission factors sufficiently promotes mitochondrial dispersion and reproductive longevity. Moreover, we discovered that bacterial inputs affect mtGTP levels and dynamics factors to modulate reproductive aging. These results demonstrate the significance of mtGTP metabolism in regulating oocyte mitochondrial homeostasis and reproductive longevity and identify mitochondrial fission induction as an effective strategy to improve reproductive health.
    Keywords:  GTP metabolism; bacteria-host interaction; gene-environment interaction; mitochondrial distribution; mitochondrial dynamics; oocyte quality control; reproductive aging; succinyl-CoA synthetase; vitamin B12
    DOI:  https://doi.org/10.1016/j.devcel.2023.08.019
  10. Cold Spring Harb Mol Case Stud. 2023 Sep 14. pii: mcs.a006295. [Epub ahead of print]
    Novel pathogenic UQCRC2 variants in a female with normal neurodevelopment.
    Lea Abou Haidar, Robert Charles Harris, Panayotis Pachnis, Hongli Chen, Garrett K Gotway, Min Ni, Ralph J DeBerardinis.
      Electron transport chain (ETC) disorders are a group of rare, multisystem diseases caused by impaired oxidative phosphorylation and energy production. Deficiencies in complex III (CIII), also known as ubiquinol-cytochrome c reductase, are particularly rare in humans. Ubiquinol-cytochrome c reductase core protein 2 (UQCRC2) encodes a subunit of CIII that plays a crucial role in dimerization. Several pathogenic UQCRC2 variants have been identified in patients presenting with metabolic abnormalities that include lactic acidosis, hyperammonemia, hypoglycemia, and organic aciduria. Almost all previously-reported UQCRC2-deficient patients exhibited neurodevelopmental involvement, including developmental delays and structural brain anomalies. Here we describe a girl who presented at 3 years of age with lactic acidosis, hyperammonemia, and hypoglycemia, but has not shown any evidence of neurodevelopmental dysfunction by age 15. Whole exome sequencing revealed compound heterozygosity for two novel variants in UQCRC2: c.1189G>A; p.Gly397Arg and c.437T>C; p.Phe146Ser. Here, we discuss the patient's clinical presentation and the likely pathogenicity of these two missense variants.
    Keywords:  Acute hyperammonemia; Decreased activity of mitochondrial complex III; Fasting hypoglycemia; Stress/infection-induced lactic acidosis
    DOI:  https://doi.org/10.1101/mcs.a006295
  11. J Physiol. 2023 Sep 12.
    Skeletal muscle mitochondria in strength athletes: meeting energy needs with mitochondrial morphological changes.
    Alyse L Lodigiani, Joseph C Morrison.
      
    Keywords:  Olympic weightlifting; mitochondria; mitochondrial morphology; powerlifting; strength training; transmission electron microscopy
    DOI:  https://doi.org/10.1113/JP285345
  12. Emerg Top Life Sci. 2023 Sep 12. pii: ETLS20230017. [Epub ahead of print]
    Friedreich's ataxia: new insights.
    Maria M Krasilnikova, Casey L Humphries, Emily M Shinsky.
      Friedreich ataxia (FRDA) is an inherited disease that is typically caused by GAA repeat expansion within the first intron of the FXN gene coding for frataxin. This results in the frataxin deficiency that affects mostly muscle, nervous, and cardiovascular systems with progressive worsening of the symptoms over the years. This review summarizes recent progress that was achieved in understanding of molecular mechanism of the disease over the last few years and latest treatment strategies focused on overcoming the frataxin deficiency.
    Keywords:   FXN gene; Frataxin; Friedreich's ataxia; GAA repeat; review
    DOI:  https://doi.org/10.1042/ETLS20230017
  13. J Transl Med. 2023 09 09. 21(1): 613
    Mitochondrial dysfunction in neurodegenerative disorders: Potential therapeutic application of mitochondrial transfer to central nervous system-residing cells.
    Felipe A Bustamante-Barrientos, Noymar Luque-Campos, María Jesús Araya, Eliana Lara-Barba, Javiera de Solminihac, Carolina Pradenas, Luis Molina, Yeimi Herrera-Luna, Yildy Utreras-Mendoza, Roberto Elizondo-Vega, Ana María Vega-Letter, Patricia Luz-Crawford.
      Mitochondrial dysfunction is reiteratively involved in the pathogenesis of diverse neurodegenerative diseases. Current in vitro and in vivo approaches support that mitochondrial dysfunction is branded by several molecular and cellular defects, whose impact at different levels including the calcium and iron homeostasis, energetic balance and/or oxidative stress, makes it difficult to resolve them collectively given their multifactorial nature. Mitochondrial transfer offers an overall solution since it contains the replacement of damage mitochondria by healthy units. Therefore, this review provides an introducing view on the structure and energy-related functions of mitochondria as well as their dynamics. In turn, we summarize current knowledge on how these features are deregulated in different neurodegenerative diseases, including frontotemporal dementia, multiple sclerosis, amyotrophic lateral sclerosis, Friedreich ataxia, Alzheimer´s disease, Parkinson´s disease, and Huntington's disease. Finally, we analyzed current advances in mitochondrial transfer between diverse cell types that actively participate in neurodegenerative processes, and how they might be projected toward developing novel therapeutic strategies.
    DOI:  https://doi.org/10.1186/s12967-023-04493-w
  14. Nat Rev Mol Cell Biol. 2023 Sep 11.
    Alternative to lysosomal degradation: mitochondrial removal via EVs.
    Paulina Strzyz.
      
    DOI:  https://doi.org/10.1038/s41580-023-00660-5
  15. IUBMB Life. 2023 Sep 15.
    Early steps in the biogenesis of mitochondrially encoded oxidative phosphorylation subunits.
    Sung-Jun Jung, Sagar Sridhara, Martin Ott.
      The complexes mediating oxidative phosphorylation (OXPHOS) in the inner mitochondrial membrane consist of proteins encoded in the nuclear or the mitochondrial DNA. The mitochondrially encoded membrane proteins (mito-MPs) represent the catalytic core of these complexes and follow complicated pathways for biogenesis. Owing to their overall hydrophobicity, mito-MPs are co-translationally inserted into the inner membrane by the Oxa1 insertase. After insertion, OXPHOS biogenesis factors mediate the assembly of mito-MPs into complexes and participate in the regulation of mitochondrial translation, while protein quality control factors recognize and degrade faulty or excess proteins. This review summarizes the current understanding of these early steps occurring during the assembly of mito-MPs by concentrating on results obtained in the model organism baker's yeast.
    Keywords:  eukaryotic gene expression; mitochondria; protein folding; protein synthesis
    DOI:  https://doi.org/10.1002/iub.2784
  16. J Biol Chem. 2023 Sep 08. pii: S0021-9258(23)02269-X. [Epub ahead of print] 105241
    Cardiolipin prolongs the lifetimes of respiratory proteins in Drosophila flight muscle.
    Mindong Ren, Yang Xu, Colin K L Phoon, Hediye Erdjument-Bromage, Thomas A Neubert, Michael Schlame.
      Respiratory complexes and cardiolipins have exceptionally long lifetimes. The fact that they co-localize in mitochondrial cristae raises the questions of whether their longevities have a common cause and whether the longevity of OXPHOS proteins is dependent on cardiolipin. To address these questions, we developed a method to measure side-by-side the half-lives of proteins and lipids in wildtype Drosophila and cardiolipin deficient mutants. We fed adult flies with stable isotope-labeled precursors (13C615N2-lysine or 13C6-glucose) and determined the relative abundance of heavy isotopomers in protein and lipid species by mass spectrometry. To minimize confounding effects of tissue regeneration, we restricted our analysis to the thorax, the bulk of which consists of post-mitotic flight muscles. Analysis of 680 protein and 45 lipid species showed that the subunits of respiratory complexes I-V and the carriers for phosphate and ADP/ATP were among the longest-lived proteins (average half-life of 48±16 days) while the molecular species of cardiolipin were the longest-lived lipids (average half-life of 27±6 days). The remarkable longevity of these crista residents was not shared by all mitochondrial proteins, especially not by those residing in the matrix and the inner boundary membrane. Ablation of cardiolipin synthase, which causes replacement of cardiolipin by phosphatidylglycerol, and ablation of tafazzin, which causes partial replacement of cardiolipin by monolyso-cardiolipin, decreased the lifetimes of the respiratory complexes. Ablation of tafazzin also decreased the lifetimes of the remaining cardiolipin species. These data suggest that an important function of cardiolipin in mitochondria is to protect respiratory complexes from degradation.
    Keywords:  Insect; isotopic tracer; lipid-protein interaction; membrane biogenesis; mitochondrial respiratory chain complex
    DOI:  https://doi.org/10.1016/j.jbc.2023.105241
  17. bioRxiv. 2023 Sep 01. pii: 2023.08.31.555756. [Epub ahead of print]
    Outer mitochondrial membrane E3 Ub ligase MARCH5 controls mitochondrial steps in peroxisome biogenesis.
    Nicolas Verhoeven, Yumiko Oshima, Etienne Cartier, Albert Neutzner, Liron Boyman, Mariusz Karbowski.
      Peroxisome de novo biogenesis requires yet unidentified mitochondrial proteins. We report that the outer mitochondrial membrane (OMM)-associated E3 Ub ligase MARCH5 is vital for generating mitochondria-derived pre-peroxisomes. MARCH5 knockout results in accumulation of immature peroxisomes and lower expression of various peroxisomal proteins. Upon fatty acid-induced peroxisomal biogenesis, MARCH5 redistributes to newly formed peroxisomes; the peroxisomal biogenesis under these conditions is inhibited in MARCH5 knockout cells. MARCH5 activity-deficient mutants are stalled on peroxisomes and induce accumulation of peroxisomes containing high levels of the OMM protein Tom20 (mitochondria-derived pre-peroxisomes). Furthermore, depletion of peroxisome biogenesis factor Pex14 leads to the formation of MARCH5- and Tom20-positive peroxisomes, while no peroxisomes are detected in Pex14/MARCH5 dko cells. Reexpression of WT, but not MARCH5 mutants, restores Tom20-positive pre-peroxisomes in Pex14/MARCH5 dko cells. Thus, MARCH5 acts upstream of Pex14 in mitochondrial steps of peroxisome biogenesis. Our data validate the hybrid, mitochondria-dependent model of peroxisome biogenesis and reveal that MARCH5 is an essential mitochondrial protein in this process.
    Summary: The authors found that mitochondrial E3 Ub ligase MARCH5 controls the formation of mitochondria-derived pre-peroxisomes. The data support the hybrid, mitochondria-dependent model of peroxisome biogenesis and reveal that MARCH5 is an essential mitochondrial protein in this process.
    DOI:  https://doi.org/10.1101/2023.08.31.555756
  18. Int J Biol Sci. 2023 ;19(13): 4327-4339
    Sirtuin-3 activates the mitochondrial unfolded protein response and reduces cerebral ischemia/reperfusion injury.
    Xie Xiaowei, Xu Qian, Zhou Dingzhou.
      Sirtuin-3 (Sirt3) deacetylates several mitochondrial proteins implicated into cerebral ischemia/reperfusion (I/R) injury. The mitochondrial unfolded protein response (UPRmt) favors mitochondrial proteostasis during various stressors. Here, we used Sirt3 transgenic mice and a transient middle cerebral artery occlusion model to evaluate the molecular basis of Sirt3 on the UPRmt during brain post-ischemic dysfunction. The present study illustrated that Sirt3 abundance was suppressed in the brain after brain ischemic abnormalities. Overexpression of Sirt3 in vivo suppressed the infarction size and attenuated neuroinflammation after brain I/R injury. Sirt3 overexpression restored neural viability by reducing mitochondrial ROS synthesis, maintaining the mitochondrial potential and improving mitochondrial adenosine triphosphate synthesis. Sirt3 overexpression protected neuronal mitochondria against brain post-ischemic malfunction via eliciting the UPRmt by the forkhead box O3 (Foxo3)/sphingosine kinase 1 (Sphk1) pathway. Inhibiting either the UPRmt or the Foxo3/Sphk1 pathway relieved the favorable influence of Sirt3 on neural function and mitochondrial behavior. In contrast, Sphk1 overexpression was sufficient to reduce the infarction size, attenuate neuroinflammation, sustain neuronal viability and prevent mitochondrial abnormalities during brain post-ischemia dysfunction. Thus, the UPRmt protects neural viability and mitochondrial homeostasis, and the Sirt3/Foxo3/Sphk1 pathway is a promosing therapeutic candidate for ischemic stroke.
    Keywords:  Foxo3; Sirt3; Sphk1; UPRmt; cerebral I/R injury; mitochondria
    DOI:  https://doi.org/10.7150/ijbs.86614
  19. Redox Biol. 2023 Sep 07. pii: S2213-2317(23)00272-0. [Epub ahead of print]67 102871
    Mesenchymal stem cell attenuates spinal cord injury by inhibiting mitochondrial quality control-associated neuronal ferroptosis.
    Senyu Yao, Mao Pang, Yanheng Wang, Xiaokang Wang, Yaobang Lin, Yanyan Lv, Ziqi Xie, Jianfeng Hou, Cong Du, Yuan Qiu, Yuanjun Guan, Bin Liu, Jiancheng Wang, Andy Peng Xiang, Limin Rong.
      Ferroptosis is a newly discovered form of iron-dependent oxidative cell death and drives the loss of neurons in spinal cord injury (SCI). Mitochondrial damage is a critical contributor to neuronal death, while mitochondrial quality control (MQC) is an essential process for maintaining mitochondrial homeostasis to promote neuronal survival. However, the role of MQC in neuronal ferroptosis has not been clearly elucidated. Here, we further demonstrate that neurons primarily suffer from ferroptosis in SCI at the single-cell RNA sequencing level. Mechanistically, disordered MQC aggravates ferroptosis through excessive mitochondrial fission and mitophagy. Furthermore, mesenchymal stem cells (MSCs)-mediated mitochondrial transfer restores neuronal mitochondria pool and inhibits ferroptosis through mitochondrial fusion by intercellular tunneling nanotubes. Collectively, these results not only suggest that neuronal ferroptosis is regulated in an MQC-dependent manner, but also fulfill the molecular mechanism by which MSCs attenuate neuronal ferroptosis at the subcellular organelle level. More importantly, it provides a promising clinical translation strategy based on stem cell-mediated mitochondrial therapy for mitochondria-related central nervous system disorders.
    Keywords:  Intercellular mitochondrial transfer; Mesenchymal stem cells; Mitochondrial quality control; Neuronal ferroptosis; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.redox.2023.102871
  20. iScience. 2023 Oct 20. 26(10): 107713
    Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a Friedreich's ataxia mouse model.
    Riccardo Turchi, Francesca Sciarretta, Veronica Ceci, Marta Tiberi, Matteo Audano, Silvia Pedretti, Concetta Panebianco, Valentina Nesci, Valerio Pazienza, Alberto Ferri, Simone Carotti, Valerio Chiurchiù, Nico Mitro, Daniele Lettieri-Barbato, Katia Aquilano.
      Friedreich's ataxia (FA) is a neurodegenerative disease resulting from a mutation in the FXN gene, leading to mitochondrial frataxin deficiency. FA patients exhibit increased visceral adiposity, inflammation, and heightened diabetes risk, negatively affecting prognosis. We investigated visceral white adipose tissue (vWAT) in a murine model (KIKO) to understand its role in FA-related metabolic complications. RNA-seq analysis revealed altered expression of inflammation, angiogenesis, and fibrosis genes. Diabetes-like traits, including larger adipocytes, immune cell infiltration, and increased lactate production, were observed in vWAT. FXN downregulation in cultured adipocytes mirrored vWAT diabetes-like features, showing metabolic shifts toward glycolysis and lactate production. Metagenomic analysis indicated a reduction in fecal butyrate-producing bacteria, known to exert antidiabetic effects. A butyrate-enriched diet restrained vWAT abnormalities and mitigated diabetes features in KIKO mice. Our work emphasizes the role of vWAT in FA-related metabolic issues and suggests butyrate as a safe and promising adjunct for FA management.
    Keywords:  Biological sciences; Natural sciences; Neuroscience; Pharmacology
    DOI:  https://doi.org/10.1016/j.isci.2023.107713
  21. Brain. 2023 Sep 13. pii: awad313. [Epub ahead of print]
    Trazodone rescues dysregulated synaptic and mitochondrial nascent proteomes in prion neurodegeneration.
    Hector Albert-Gasco, Heather L Smith, Beatriz Alvarez-Castelao, Dean Swinden, Mark Halliday, Sudha Janaki-Raman, Adrian Butcher, Giovanna R Mallucci.
      The unfolded protein response (UPR) is rapidly gaining momentum as a therapeutic target for protein misfolding neurodegenerative diseases, in which its overactivation results in sustained translational repression leading to synapse loss and neurodegeneration. In mouse models of these disorders, from Alzheimer's to prion disease, modulation of the pathway - including by the licensed drug, trazodone - restores global protein synthesis rates with profound neuroprotective effects. However, the precise nature of the translational impairment, in particular the specific proteins affected in disease, and their response to therapeutic UPR modulation are poorly understood. We used non-canonical amino acid tagging (NCAT) to measure de novo protein synthesis in the brains of prion-diseased mice with and without trazodone treatment, in both whole hippocampus and cell-specifically. During disease the predominant nascent proteome changes occur in synaptic, cytoskeletal and mitochondrial proteins in both hippocampal neurons and astrocytes. Remarkably, trazodone treatment for just two weeks largely restored the whole disease nascent proteome in the hippocampus to that of healthy, uninfected mice, predominantly with recovery of proteins involved in synaptic and mitochondrial function. In parallel, trazodone treatment restored the disease-associated decline in synapses and mitochondria and their function to wildtype levels. In conclusion, this study increases our understanding of how translational repression contributes to neurodegeneration through synaptic and mitochondrial toxicity via depletion of key proteins essential for their function. Further, it provides new insights into the neuroprotective mechanisms of trazodone through reversal of this toxicity, relevant for the treatment of neurodegenerative diseases via translational modulation.
    Keywords:  UPR/ISR; mitochondria; nascent proteome; neurodegeneration; synapses; translational repression; trazodone
    DOI:  https://doi.org/10.1093/brain/awad313
  22. Free Radic Biol Med. 2023 Sep 13. pii: S0891-5849(23)00627-5. [Epub ahead of print]
    Nrf2 depletion in the context of loss-of-function Keap1 leads to mitolysosome accumulation.
    Sharadha Dayalan Naidu, Plamena R Angelova, Elena V Knatko, Chiara Leonardi, Miroslav Novak, Laureano de la Vega, Ian G Ganley, Andrey Y Abramov, Albena T Dinkova-Kostova.
      Transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) is the principal determinant of the cellular redox homeostasis, contributing to mitochondrial function, integrity and bioenergetics. The main negative regulator of Nrf2 is Kelch-like ECH associated protein 1 (Keap1), a substrate adaptor for Cul3/Rbx1 ubiquitin ligase, which continuously targets Nrf2 for ubiquitination and proteasomal degradation. Loss-of-function mutations in Keap1 occur frequently in lung cancer, leading to constitutive Nrf2 activation. We used the human lung cancer cell line A549 and its CRISPR/Cas9-generated homozygous Nrf2-knockout (Nrf2-KO) counterpart to assess the role of Nrf2 on mitochondrial health. To confirm that the observed effects of Nrf2 deficiency are not due to clonal selection or long-term adaptation to the absence of Nrf2, we also depleted Nrf2 by siRNA (siNFE2L2), thus creating populations of Nrf2-knockdown (Nrf2-KD) A549 cells. Nrf2 deficiency decreased mitochondrial respiration, but increased the mitochondrial membrane potential, mass, DNA content, and the number of mitolysosomes. The proportion of ATG7 and ATG3 within their respective LC3B conjugates was increased in Nrf2-deficient cells with mutant Keap1, whereas the formation of new autophagosomes was not affected. Thus, in lung cancer cells with loss-of-function Keap1, Nrf2 facilitates mitolysosome degradation thereby ensuring timely clearance of damaged mitochondria.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.09.009
  23. Nat Metab. 2023 Sep 11.
    Molecular control of endurance training adaptation in male mouse skeletal muscle.
    Regula Furrer, Barbara Heim, Svenia Schmid, Sedat Dilbaz, Volkan Adak, Karl J V Nordström, Danilo Ritz, Stefan A Steurer, Jörn Walter, Christoph Handschin.
      Skeletal muscle has an enormous plastic potential to adapt to various external and internal perturbations. Although morphological changes in endurance-trained muscles are well described, the molecular underpinnings of training adaptation are poorly understood. We therefore aimed to elucidate the molecular signature of muscles of trained male mice and unravel the training status-dependent responses to an acute bout of exercise. Our results reveal that, even though at baseline an unexpectedly low number of genes define the trained muscle, training status substantially affects the transcriptional response to an acute challenge, both quantitatively and qualitatively, in part associated with epigenetic modifications. Finally, transiently activated factors such as the peroxisome proliferator-activated receptor-γ coactivator 1α are indispensable for normal training adaptation. Together, these results provide a molecular framework of the temporal and training status-dependent exercise response that underpins muscle plasticity in training.
    DOI:  https://doi.org/10.1038/s42255-023-00891-y
  24. Nat Rev Genet. 2023 Sep 15.
    Illuminating the human yolk sac through single-cell omics.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41576-023-00658-x
  25. Nat Commun. 2023 Sep 15. 14(1): 5714
    Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation.
    Junhao Li, Manoj K Jaiswal, Jo-Fan Chien, Alexey Kozlenkov, Jinyoung Jung, Ping Zhou, Mahammad Gardashli, Luc J Pregent, Erica Engelberg-Cook, Dennis W Dickson, Veronique V Belzil, Eran A Mukamel, Stella Dracheva.
      A repeat expansion in the C9orf72 (C9) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we investigate single nucleus transcriptomics (snRNA-seq) and epigenomics (snATAC-seq) in postmortem motor and frontal cortices from C9-ALS, C9-FTD, and control donors. C9-ALS donors present pervasive alterations of gene expression with concordant changes in chromatin accessibility and histone modifications. The greatest alterations occur in upper and deep layer excitatory neurons, as well as in astrocytes. In neurons, the changes imply an increase in proteostasis, metabolism, and protein expression pathways, alongside a decrease in neuronal function. In astrocytes, the alterations suggest activation and structural remodeling. Conversely, C9-FTD donors have fewer high-quality neuronal nuclei in the frontal cortex and numerous gene expression changes in glial cells. These findings highlight a context-dependent molecular disruption in C9-ALS and C9-FTD, indicating unique effects across cell types, brain regions, and diseases.
    DOI:  https://doi.org/10.1038/s41467-023-41033-y
  26. Am J Respir Cell Mol Biol. 2023 Sep 15.
    Mitochondria Derived Vesicle Packaging as a Novel Therapeutic Mechanism in Pulmonary Hypertension.
    Qiang Zhao, Zhixue Liu, Ping Song, Zuyi Yuan, Ming-Hui Zou.
      Increasing evidence suggests that mitochondrial dysfunction in pulmonary endothelial cells (ECs) plays a causative role in the initiation and progression of pulmonary hypertension (PH); how mitochondria become dysfunctional in PH remains elusive. Mitochondria-derived vesicles (MDVs) are small subcellular vesicles that excise from mitochondria. Whether or not MDVs deregulation causes mitochondrial dysfunction in PH is unknown. This aim of this study was to determine MDVs regulation in ECs and to elucidate how MDVs deregulation in ECs leads to PH. MDVs formation and mitochondrial morphology/dynamics were examined in ECs of the EC-specific-Liver kinase B1 (LKB1) knock out mice (LKB1ec-/-), in monocrotaline (MCT)-induced PH rats, and in lungs of patients with PH. Pulmonary ECs of PH patients and hypoxia-treated pulmonary ECs exhibited increased mitochondrial fragmentation and disorganized mitochondrial ultrastructure characterized by electron lucent-swelling matrix compartments and concentric layering of cristae network, along with defective MDVs shedding. MDVs actively regulated mitochondrial membrane dynamics and mitochondrial ultrastructure via its removing mitofission-related cargoes. The shedding of MDVs from parental mitochondria required LKB1-mediated mitochondrial recruitment of Rab9 GTPase. LKB1ec-/- mice spontaneously developed PH with decreased mitochondrial pools of Rab9 GTPase, defective MDVs shedding, and disequilibrium of mitochondrial fusion-fission cycle in pulmonary ECs. Aerosol intra-tracheal delivery of adeno-associated virus LKB1 reversed PH, along with improved MDVs shedding and mitochondrial functions in rats in vivo. We conclude that LKB1 regulates MDVs shedding and mitochondrial dynamics in pulmonary ECs by enhancing mitochondrial recruitment of Rab9 GTPase. Defect of LKB1-mediated MDVs shedding from parental mitochondria instigates ECs dysfunction and PH.
    Keywords:  Pulmonary hypertension , Endothelial dysfunction , Mitochondria derived vesicles , Liver kinase B1
    DOI:  https://doi.org/10.1165/rcmb.2023-0010OC
  27. Arch Gerontol Geriatr. 2023 Sep 01. pii: S0167-4943(23)00254-6. [Epub ahead of print]117 105176
    The association between methylmalonic acid, a biomarker of mitochondria dysfunction, and phenotypic age acceleration: A population-based study.
    Bing Cao, Yu Xue, Dan Liu.
      Phenotypic age acceleration (PAA) is a sensitive marker of biological aging. Circulating methylmalonic acid (MMA) is a novel biomarker of mitochondrial dysfunction and has been associated with age-related disorders. Our study aimed to investigate to what extent circulating MMA was associated with PAA, and whether the association was independent of vitamin B12 status and renal function in the general population. We analyzed cross-sectional data from 13,023 participants across a wide age range (mean age: 38.9 years, range: 12 - 85 years, 51.1% women) from the US National Health and Nutrition Examination Survey (NHANES). PAA was calculated based on the published algorithm. Linear regression models were performed to assess the association between circulating MAA and PAA. Only 31% of the variation in MMA levels was explained by age, sex, race/ethnicity, social economic status, vitamin B12 status, and renal function. Per unit increase in circulating MAA (1.0 nmol/L) was associated with 1.59 years increase in PAA (β = 1.59, 95% CI: 1.17, 2.00, p < 0.001) after adjusting for multiple confounders. Importantly, PAA increased with circulating MMA levels independent of vitamin B12, creatine, and homocysteine levels. The association was more pronounced in subgroups of age ≥ 65 years, women, underweight, vitamin B12 < 400 μmol/L, and homocysteine ≥ 10 μmol/L. The association was much stronger among participants with cardiovascular diseases (CVDs) than without CVDs. In conclusion, our current population-based study showed that mitochondria-derived circulating MMA was associated with increased phenotypic age acceleration in the general population.
    Keywords:  Biological aging; Methylmalonic acid; Mitochondria; Phenotypic age
    DOI:  https://doi.org/10.1016/j.archger.2023.105176
  28. Front Neurol. 2023 ;14 1239664
    A patient with MELAS syndrome combined with autoimmune abnormalities: a case report.
    Mingmin Zhao, Chun Zuo, Hongyu Hao, Xing Xing, Lei Zhao, Na Li.
       Background: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a group of maternally inherited disorders caused by mutations or deletions in mitochondrial genes with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes as the main clinical manifestations.
    Case presentation: We reported a 20-year-old female patient with MELAS syndrome combined with autoimmune abnormalities. She suffered from an intermittent headache in the right temporal region with no obvious cause, and then, after strenuous exercise in dance class, the headache became aggravated, accompanied by unresponsiveness, blurred vision, and diplopia. Her blood lactate levels were elevated, her antinuclear antibodies were positive, and the antimetabolic glutamate receptors 5 in her serum were positive. Brain DWI showed a hypertensive signal in the right temporo-parietal-occipital cortex and subcortical area. Brain MRS showed decreased NAA peak and increased Lac peak. Muscle biopsy showed myogenic damage, and the modified Gomori trichrome (MGT) staining showed ragged red fibers (RRF). A genetic study revealed a mitochondrial DNA A3243G mutation.
    Conclusion: Mitochondrial encephalomyopathy is a rare clinical condition; however, the association with autoimmune diseases is not yet clear and still needs further research and analysis.
    Keywords:  MELAS; antimetabolic glutamate receptor 5 encephalitis; antinuclear antibodies (ANA); autoimmune abnormalities; mitochondrial encephalomyopathy
    DOI:  https://doi.org/10.3389/fneur.2023.1239664
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